Defective bone mechanosensing and skeletal unloading contribute to age-related and disuse osteoporosis. The molecular mechanisms that transduce the osteoblast response to physical forces in the bone microenvironment to maintain skeletal homeostasis are poorly understood. We discovered a novel mechanosensing complex in osteoblasts created by an interaction between polycystins (PC1, Pkd1 and PC2, Pkd2) and TAZ (transcriptional coactivator with PDZ-binding motif). The PC1/PC2/TAZ complex functions to sense and transduce mechanical loading into anabolic bone responses. Loss of either Pkd1 or Taz in mice results in osteopenia characterized by a reciprocal decrease in osteoblast-mediated bone formation and an increase in adipocytes in bone marrow. Compound heterozygous mice lacking one copy of Pkd1 and TAZ exhibit additive decrements in bone mass, impaired osteoblast-mediated bone formation and enhanced accumulation of bone marrow fat. The PC1 C-ter- minal tail (PC1-CTT) binds to and facilitates TAZ nuclear translocation to co-activate Runx2-mediated osteoblas- togenesis and co-repress PPAR?-mediated adipogenesis in vitro. Computational approaches using structure- based virtual screening discovered a novel agonist (mechanomimetic) that binds to the PC1:PC2 C-terminal tail helix: helix interaction region and activates polycystins/TAZ signaling. These observations provide the scientific premise for the hypothesis that skeletal responses to loading are transduced by a mechanosensing complex in osteoblasts formed by interactions between PC1, PC2 and TAZ. Aim 1 tests the hypothesis that Pkd1/TAZ have interdependent functions in mature osteoblasts to regulate bone mass through the reciprocal stimulation of os- teoblastogenesis and inhibition of adipogenesis. In this aim, we will examine the effects of TAZ to differentially regulate osteoblastogenesis and adipogenesis in vitro and in vivo by creating mice with conditional knockout of Taz in mature osteoblasts (TazOc-cko). We will further test for genetic interactions between Taz and Pkd1 by creating compound Pkd1Oc-cko/Taz Oc-cko mice. Aim 2 tests the hypothesis that the Pkd1/TAZ complex mediates the response of osteoblasts to mechanical loading in vivo and in vitro using single and compound Pkd1 and Taz loss-of-function mouse models and osteoblast cultures. Aim 3 tests the hypothesis that activation of the PC1/PC2/TAZ with a novel ?mechanomimetic? will increase bone mass by stimulating osteoblastogenesis and inhibiting adipogenesis. Our impact will be to provide a new understanding of the molecular mechanisms medi- ating the skeletal response to loading by validating the PC1/PC2/TAZ mechanosensing complex in osteoblasts. In this new schema, PC1-CTT and TAZ form an integrative mechanosensing complex in cells within the osteo- blast lineage to differentially regulate Runx2-dependent osteoblastogenesis and PPAR?-mediated adipogenesis in response to physical cues in the bone microenvironment. The polycystins/TAZ complex is also a potential therapeutic target for treating osteoporosis caused by skeletal unloading; and the newly discovered first-in-class mechanomimetic provides a chemical probe to test if targeting polycystins/TAZ results in increased bone mass.